{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T11:08:21Z","timestamp":1775732901514,"version":"3.50.1"},"posted":{"date-parts":[[2026,4,6]]},"group-title":"Physiology","reference-count":40,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T00:00:00Z","timestamp":1775433600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"American Cancer Society Institutional Research Grant","award":["IRG-21-146-25"],"award-info":[{"award-number":["IRG-21-146-25"]}]},{"name":"National Cancer Institute","award":["P30CA118100"],"award-info":[{"award-number":["P30CA118100"]}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"crossref","award":["P20GM121176"],"award-info":[{"award-number":["P20GM121176"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"crossref","award":["GM144834"],"award-info":[{"award-number":["GM144834"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100006108","name":"National Center for Advancing Translational Sciences","doi-asserted-by":"crossref","award":["UL1TR001449"],"award-info":[{"award-number":["UL1TR001449"]}],"id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Metabolic syndrome (MetS), characterized by abdominal obesity, insulin resistance, dyslipidemia, and hypertension, affects a substantial proportion of the global population and increases the risk for cardiovascular disease, diabetes, and metabolic dysfunction-associated steatotic liver disease (MASLD). Despite its prevalence, there are currently no effective pharmacological therapies targeting MetS, highlighting the need to identify novel etiological mechanisms, particularly within the gastrointestinal (GI) tract. Using a mouse model of MetS and healthy lean controls, we assessed the colonic microenvironment through metabolomic, transcriptomic, and microbiome analyses. Colonic organoids were cultured to further explore epithelial alterations. Additionally, human MetS fecal metabolomics data were cross-compared with the mouse model to validate translational relevance. MetS mice exhibited upregulation of colonic anabolic pathways, including glycolysis, the pentose phosphate pathway, and the tryptophan\/kynurenine pathway, without evidence of intestinal inflammation. Microbiome analysis revealed an increased abundance of the genus\n                  <jats:italic>Lactobacillus<\/jats:italic>\n                  in MS NASH mice. Colonic organoids from MetS mice showed altered goblet cell differentiation. Comparative analysis with human MetS fecal metabolomics demonstrated similar dysregulated pathways, underscoring the translational relevance of these findings. Our study reveals significant metabolic and microbial alterations in the colon of MS NASH mice, implicating a dysfunctional GI tract as a potential etiological factor in MetS. These findings highlight specific metabolic pathways and microbial signatures that could serve as future therapeutic targets for MetS.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>NEW &amp; NOTEWORTHY<\/jats:title>\n                  <jats:p>This study identifies the colon as a metabolically active tissue affected in metabolic syndrome. Despite the absence of intestinal inflammation, MS NASH mice displayed altered colonic metabolism and microbiota composition, with conserved metabolite changes matching those seen in humans with metabolic syndrome. These findings highlight colonic metabolic dysfunction as a potential driver of gut dysbiosis and disease progression in metabolic syndrome and MASLD.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Graphical Abstract<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"716131v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.64898\/2026.04.02.716131","type":"posted-content","created":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T22:30:14Z","timestamp":1775514614000},"source":"Crossref","is-referenced-by-count":0,"title":["Colonic metabolomic and transcriptomic alterations in a mouse model of metabolic syndrome"],"prefix":"10.64898","author":[{"given":"Jaclyn A.","family":"Rivas","sequence":"first","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of New Mexico Health Sciences, Albuquerque, NM"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David P.","family":"Scieszka","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of New Mexico Health Sciences, Albuquerque, NM"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eduardo","family":"Peralta-Herrera","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of New Mexico Health Sciences, Albuquerque, NM"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Crystal Madera","family":"Enriquez","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of New Mexico Health Sciences, Albuquerque, NM"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4987-1195","authenticated-orcid":false,"given":"Seth D.","family":"Merkley","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of New Mexico Health Sciences, Albuquerque, NM"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Audrey L.","family":"Nava","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of New Mexico Health Sciences, Albuquerque, NM"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4441-1402","authenticated-orcid":false,"given":"Rama R.","family":"Gullapalli","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of New Mexico Health Sciences, Albuquerque, NM"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5083-560X","authenticated-orcid":false,"given":"Eliseo F.","family":"Castillo","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of New Mexico Health Sciences, Albuquerque, NM"},{"name":"Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026040903250542000_2026.04.02.716131v1.1","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1177\/1074248416686187","article-title":"Metabolic Syndrome","volume":"22","year":"2017","journal-title":"J Cardiovasc Pharmacol Ther"},{"key":"2026040903250542000_2026.04.02.716131v1.2","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.cld.2017.08.010","article-title":"Nonalcoholic Fatty Liver Disease and Metabolic Syndrome","volume":"22","year":"2018","journal-title":"Clin Liver Dis"},{"key":"2026040903250542000_2026.04.02.716131v1.3","doi-asserted-by":"crossref","first-page":"3246","DOI":"10.4103\/jfmpc.jfmpc_1108_19","article-title":"Prevalence of fatty liver in metabolic syndrome","volume":"9","year":"2020","journal-title":"J Family Med Prim Care"},{"key":"2026040903250542000_2026.04.02.716131v1.4","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1016\/S2213-8587(14)70032-4","article-title":"Non-alcoholic fatty liver disease as a cause and a consequence of metabolic syndrome","volume":"2","year":"2014","journal-title":"Lancet Diabetes Endocrinol"},{"key":"2026040903250542000_2026.04.02.716131v1.5","doi-asserted-by":"crossref","unstructured":"Coleman MJ , Espino LM , Lebensohn H , Zimkute MV , Yaghooti N , Ling CL , Gross JM , Listwan N , Cano S , Garcia V , Lovato DM , Tigert SL , Jones DR , Gullapalli RR , Rakov NE , Torrazza Perez EG , and Castillo EF . Individuals with Metabolic Syndrome Show Altered Fecal Lipidomic Profiles with No Signs of Intestinal Inflammation or Increased Intestinal Permeability. 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